The SOCS box of suppressor of cytokine signaling-3 contributes to the control of G-CSF responsiveness in vivo

Boyle, K; Egan, P; Rakar, S; Willson, TA; Wicks, IP; Metcalf, D; Hilton, DJ; Nicola, NA; Alexander, WS; Roberts, AW; Robb, L

Author(s): Boyle, K; Egan, P; Rakar, S; Willson, TA; Wicks, IP; Metcalf, D; Hilton, DJ; Nicola, NA; Alexander, WS; Roberts, AW; Robb, L;
Details: Publication Year 2007-09-01,Volume 110,Issue #5,Page 1466-1474
Journal Title: BLOOD
Publication Type: Journal Article
Abstract: Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of granulocyte-colony stimulating factor (G-CSF) signaling in vivo. SOCS proteins regulate cytokine signaling by binding, via their SH2 domains, to activated cytokine receptors or their associated Janus kinases. In addition, they bind to the elongin B/C ubiquitin ligase complex via the SOCS box. To ascertain the contribution of the SOCS box of SOCS3 to in vivo regulation of G-CSF signaling, we generated mice expressing a truncated SOCS3 protein lacking the C-terminal SOCS box (SOCS3(Delta SB/Delta SB)). SOCS3(Delta SB/Delta SB) mice were viable, had normal steady-state hematopoiesis, and did not develop inflammatory disease. Despite the mild phenotype, STAT3 activation in response to G-CSF signaling was prolonged in SOCS3(Delta SB/Delta SB) bone marrow. SOCS3(Delta SB/Delta SB) bone marrow contained increased numbers of colony forming cells responsive to G-CSF and IL-6. Treatment of the mice with pharmacologic doses of G-CSF, which mimics emergency granulopoiesis and therapeutic use of G-CSF revealed that SOCS3(Delta SB/Delta SB) mice were hyperresponsive to G-CSF. Compared with wild-type mice, SOCS3(Delta SB/Delta SB) mice developed a more florid arthritis when tested using an acute disease model. Overall, the results establish a role for the SOCS box of SOCS3 in the in vivo regulation of G-CSF signaling and the response to inflammatory stimuli.
Publisher: AMER SOC HEMATOLOGY
Keywords: COLONY-STIMULATING FACTOR; PHYSIOLOGICAL NEGATIVE REGULATOR; LEUKEMIA-INHIBITORY FACTOR; JANUS TYROSINE KINASE; INFLAMMATORY ARTHRITIS; FACTOR-RECEPTOR; SH2 DOMAIN; MEDIATED DEGRADATION; PROGENITOR CELLS; PROTEINS
Publisher's Version: https://doi.org/10.1182/blood-2007-03-079178
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Creation Date: 2007-09-01 12:00:00